Schachterb,c,d,⁎ , Joseph Sirvene, Roger Porterf,g a Department of Neurology, New York University Langone Medical Center, New York, NY, USA b Department of Neurology, Beth Israel Deacone
Trang 1Conference Proceedings
The Epilepsy Foundation's 4th Biennial Epilepsy Pipeline
Update Conference
Jacqueline A Frencha, Steven C Schachterb,c,d,⁎ , Joseph Sirvene, Roger Porterf,g
a
Department of Neurology, New York University Langone Medical Center, New York, NY, USA
b Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA
c
Department of Neurology, Harvard Medical School, Boston, MA, USA
d
Consortia for Improving Medicine Through Innovation and Technology, Boston, MA, USA
e
Department of Neurology, Mayo Clinic Scottsdale, Scottsdale, AZ, USA
f
Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
g
Department of Pharmacology, USUHS, Bethesda, MD, USA
a b s t r a c t
a r t i c l e i n f o
Article history:
Received 2 February 2015
Accepted 9 February 2015
Available online xxxx
Keywords:
Epilepsy
Seizure
Therapies
Devices
Diagnostics
Innovation
Food and Drug Administration
Pipeline
On June 5 and 6, 2014, the Epilepsy Foundation held its 4th Biennial Epilepsy Pipeline Update Conference, an ini-tiative of the Epilepsy Therapy Project, which showcased the most promising epilepsy innovations from health-care companies and academic laboratories dedicated to pioneering and advancing drugs, biologics, technologies, devices, and diagnostics for epilepsy Speakers and attendees included emerging biotech and medical technology companies, major pharmaceutical and device companies, as well as investigators and innovators at the cutting-edge of epilepsy The program included panel discussions on collaboration between small and large companies, how to get products in need of funding to the marketplace, who is currently funding epilepsy and CNS innovation, and how the NIH facilitates early-stage drug development Finally, the conference featured the third annual
“Shark Tank” competition The presentations are summarized in this paper, which is followed by a compilation
of the meeting poster abstracts
© 2015 Elsevier Inc All rights reserved
1 Introduction
On June 5 and 6, 2014, the Epilepsy Foundation (EF), based in
Landover, Maryland, USA, held its 4th Biennial Epilepsy Pipeline Update
Conference, an initiative of the Epilepsy Therapy Project, at the Hyatt
Regency in San Francisco, California Showcasing the most promising
epilepsy therapies from health-care companies and academic
laborato-ries dedicated to pioneering and advancing drugs, biologics,
technolo-gies, and devices for epilepsy, this conference also featured the third
annual“Shark Tank” competition On the day following the Pipeline
conference, a day-long program was held for people with epilepsy,
fam-ilies, and advocates
The Epilepsy Pipeline Update Conference brought together
decision-makers with shared interests in epilepsy treatment and diagnosis and
product development Speakers and attendees included emerging
bio-tech and medical bio-technology companies, major pharmaceutical and
de-vice companies, as well as investigators and innovators at the
cutting-edge of epilepsy and advances in treatment of central nervous system
(CNS) diseases
The program also included panel discussions on topics such as the role
of collaboration between small and large companies, how to get products
in need of funding to the marketplace, who is funding epilepsy and CNS in-novation today, and how the NIH facilitates early-stage drug development
“The Epilepsy Foundation's Pipeline Conference is recognized as the premier business and scientific forum for driving innovation in the field
of epilepsy and neurology,” said Philip M Gattone, President and CEO of the Epilepsy Foundation.“Each year, this conference brings together great minds in R&D, clinical thought leaders, investors, and industry leaders who are focused on accelerating epilepsy drug and device development.”
“This conference has grown to attract an impressive audience Com-panies are recognizing the need for and promise in developing potential new therapeutics for epilepsy,” said Jacqueline French, MD, Professor of Neurology, New York University
The“Shark Tank” competition, held on the second day of the confer-ence, is designed to spur breakthroughs that will change the lives of people living with epilepsy Over the past two years, entrepreneurs, scientists, clinicians, industrial design engineers, and members of the epilepsy community have been recognized for their truly inventive product concepts, which have ranged from promising new therapeutics
or technologies to new products that improve the quality of life for peo-ple living with epilepsy At the 2014 Epilepsy Pipeline Conference, the
Epilepsy & Behavior xxx (2015) xxx–xxx
⁎ Corresponding author at: 165 Cambridge St, Suite 702, Boston, MA 02114, USA.
Tel.: +1 617 643 3835.
E-mail address: sschacht@bidmc.harvard.edu (S.C Schachter).
http://dx.doi.org/10.1016/j.yebeh.2015.02.033
1525-5050/© 2015 Elsevier Inc All rights reserved.
Contents lists available atScienceDirect
Epilepsy & Behavior
j o u r n a l h o m e p a g e :w w w e l s e v i e r c o m / l o c a t e / y e b e h
Trang 2winner was selected by live audience vote from the epilepsy community
and a panel of distinguished reviewers The Shark Tank award recipients
received international recognition and cash prizes totaling $200,000 to
fund the development of novel ideas
The authors of this report attended the conference and wrote
the text based on hearing the presentations at the conference as
well as reviewing the meeting recordings (http://www.epilepsy.com/
which are recommended to readers interested in more details as well as
the question-and-answer sessions Most but not all of the presentation
summaries were reviewed for accuracy by speakers The affiliations
and titles of authors are accurate as of the date of their presentation,
but may have since changed
2 Session 1: introduction and keynote address
2.1 Introduction Philip Gattone, President and Chief Executive Officer,
Epilepsy Foundation; Warren Lammert, Chairman, Board of Directors,
Epilepsy Foundation
Mr Phillip Gattone, CEO and President of EF, opened the conference
Mr Gattone remarked that this Pipeline Conference is thefirst to be
webcast (
http://www.epilepsy.com/information/professionals/epilepsy-foundation-events-webcasts) and streamed live overEpilepsy.com He
welcomed all participants and stressed the importance of this conference,
which helps to uniquely unify the epilepsy community with active
participation from patient advocates, venture capitalists, basic scientists,
pharmaceutical and device industry companies, and clinicians Mr
Gattone then introduced Mr Warren Lammert, Chairman of the Epilepsy
Foundation Board of Directors Mr Lammert also welcomed all
partici-pants to this unique conference and highlighted how this conference
fur-thers the vision of the Epilepsy Foundation research mission in order to
help bolster the translation of novel ideas into new treatments for
pa-tients with epilepsy in an expedited manner
2.2 The annual state of the drug pipeline— keynote Jacqueline French,
MD, Professor of Neurology, New York University; Co-director, Epilepsy
Research and Epilepsy Clinical Trials, NYU Comprehensive Epilepsy
Center; President, Epilepsy Study Consortium
Dr French highlighted the fact that although there are many
treat-ments that have become available for epilepsy, there is still a paucity
of treatment for those who have drug-resistant epilepsy and for
numer-ous epilepsy syndromes In particular, she pointed out that a better way
to predict the effectiveness of various drugs is needed There are still too
few options for newly diagnosed patients as many of the advances in
epilepsy management are directed to those with drug-resistant
epilep-sy In addition, there is a paucity of treatments for the comorbidities of
epilepsy Even more importantly, there are no therapies that truly
pre-vent the disease Most treatments are geared towards the concept of
preventing further seizures but we do not have any antiepileptogenic
or disease-modifying therapies Even when a drug is approved, neither
animal models nor clinical trials predict if a drug will be successful in
day-to-day clinical practice Despite many new approved antiepileptic
drugs (AEDs), there are few in phase II trials[1] Dr French summarized
her presentation by reminding the audience that so much more work is
needed to discover new AEDs with the ability to truly help patients
2.3 Annual state of the device pipeline— keynote Robert Fisher, MD, PhD,
Maslah Saul Professor of Neurology, Director, Stanford Comprehensive
Epilepsy Program
Dr Fisher divided his comments into different categories of devices
Specifically, he discussed seizure alerts or predictors; adherence
moni-tors; clinical information systems; optical control or optogenetics;
new ways of drug delivery; focal energy such as radiosurgery, laser, and ultrasound; and neurostimulation
Regarding seizure alerts, SmartWatch and EpiAlert are currently available These devices alert caregivers of seizures via wireless mobile phones or PDAs Novel systems that alert patients and caregivers to their seizures are being devised These systems operate on seizure detection by electrodermal responses, muscle activity by electromyog-raphy, or electroencephalography (EEG) patches[2–4] For seizure pre-diction, a device is in trials in which implantable EEG leads are placed in the area of a seizure focus which attach to a personal advisory device that alerts patients when a seizure is likely to occur[5]
Adherence monitors are compliance-alerting devices with the ability
to instantly provide information about pill-taking, blood test readouts of AED levels, or even when a pill reaches the stomach Related to compli-ance devices are seizure diaries with three currently available online ep-ilepsy diaries: My Epep-ilepsy Diary,Seizuretracker.com, and Patients Like Me
These diary applications help to better provide information to health-care practitioners and to the patients themselves as self-management tools
Optogenetics is a promising technique where light-induced signals can either excite or inhibit neuronal activity, carrying with it the prom-ise of enhancing epilepsy management One of the provided examples was the idea of using a yellow light that activates a rhodopsin gene, which in turn opens a chloride channel, hyperpolarizing a transfected neuron and rapidly stopping the neuron fromfiring[6]
There are a number of therapeutic devices with the ability to deliver treatment by novel approaches including inhalation, buccal absorption, and infusion pumps Focal energy can also be delivered to ablate epi-leptic tissue, such as with stereotactic radiosurgery or thermal ablation [7] Focused ultrasound is a very new potential treatment with some promise Lastly, various neuromodulatory techniques, including vagus nerve stimulation, transcranial magnetic brain stimulation, trigeminal nerve stimulation, thalamic deep brain stimulation, and responsive neurostimulation, are either currently available or being trialed[8,9]
3 Session 2: what was better in 2013 than 2012— progress in epilepsy therapy
3.1 FDA and epilepsy trials: past, present, and future Russell Katz, MD, Consultant, Epilepsy Study Consortium
Dr Russell Katz, consultant to the Epilepsy Study Consortium and former Food and Drug Administration (FDA) official, discussed the FDA and epilepsy trials: past, present, and future He noted that in par-ticular, there are four areas in which the FDA is considering new forms
of acceptable data: monotherapy indication, pediatric indication, design
of add-on trials, and controlled released products
Monotherapy claims are difficult to attain because of the ethical concerns about performing trials where standard of care is withdrawn for the drug being studied, and further, it has been difficult to extrapo-late information from add-on trials He pointed out problems with not accepting equivalence trials, yet companies want to have a
monothera-py claim A white paper has been drafted, and the FDA is reviewing it in order to address these issues and look for novel ways to approve a monotherapy indication, including possibly extrapolating from add-on studies, if proper dosing information is available
Pediatric claims have always required that a clinical trial be per-formed in pediatric patients However, pediatric claims based on adult clinical trials can be made, assuming the disease is similar in both the adults and children in a sufficient manner that one could make that claim in a reliable and safe manner, and that pediatric dosing could be provided However, to date, these criteria have not been considered to have been met Therefore, the FDA is working onfinding novel ways
to establish those claims, including the possibility that extrapolation from adult data might be acceptable
Trang 3Add-on trials themselves are now being rethought as a result of a
re-cent meta-analysis by Ryvlin[9.5]in which SUDEP risk was shown to be
lower in clinical trials for those who were randomized to effective drugs
compared to those randomized to placebo This led to the concern that
the current add-on trial design is not ethically viable Therefore, the FDA
is working on new ways to assess novel endpoints, such as time to the
nth seizure as opposed to the current manner in which the studies are
assessed
Dr Katz also addressed approval of controlled release products,
spe-cifically the requirement that controlled trials need to be done in order
to show that a controlled release product is effective Recently, a study
of an extended release topiramate was able to show that at all points
during the day (not just at Cmaxand total AUC), the plasma levels and
partial AUCs met bioequivalence criteria compared to the levels of
im-mediate release Topamax (topiramate) This led to the approval of the
controlled released product Dr Katz summarized by saying that the
FDA continues to work tofind better ways to assess drug trials and
im-prove the approval process for AEDs
3.2 Why industry should keep investing in epilepsy Christopher Gallen,
MD, PhD, President and Chief Executive Officer, SK Biopharmaceuticals, SK
Life Sciences
Dr Christopher Gallen, President and Chief Executive Officer, SK
Biopharmaceuticals, SK Life Sciences, stated the case for why industry
should keep investing in epilepsy, noting that the short answer to the
question is that“we can succeed” He said that the success rates of
CNS therapeutics are relatively low when compared to other disease
states like infectious diseases because those areas are comparatively
simple with core pathology largely internal to a single cell Nervous
sys-tem disorders involve far more complex syssys-tems, composed of many
cells, transmitters, and regulatory systems and a core pathology
involv-ing systems of cells— consequently, these disorders are not as amenable
to simple target-oriented in vitro or cellular screening models, and they
are better addressed by targeting modulation of pathophysiological
pro-cesses rather than point targets
Epilepsy, he pointed out, is not simple Existing animal predictive
models have limitations in that they test specific pathophysiological
mechanisms in a complex system but do not mimic the entirety of any
human pathology But the animal and human screening models have
significant predictive utility even with their limitations, more so than
al-most any other CNS area Of critical importance, in epilepsy, when the
drug works, high quality clinical trials typically work Trial success is
much more problematic in many CNS areas such as depression where
even known effective drugs often fail in large clinical trials This makes
epilepsy a greatfirst indication to assess the effectiveness of certain
novel medication mechanisms
He also noted that while existing AEDs are useful, epilepsy remains a
great market with a major unmet medical need— particularly to move
from reduction of numbers of seizures to the goal of complete seizure
cessation He pointed out that economic growth in Asia and elsewhere
from the changing demographics together with the spread of capitalism
is driving the availability of modern medicine to billions of people in
new corners of the world, opening the opportunity to serve a huge
new market that will ultimately exceed all existing markets combined
In terms of prescription number, nervous system disorders are the
larg-est therapeutic area The emergence of genuinely superior next
genera-tion proprietary therapies will overcome crowded markets, pricing
pressure, and generic erosion, and their commercial success will fund
the development of future generations of ever-improving therapeutics
until the scourge of epilepsy is contained Epilepsy is a large initial
mar-ket, and the fact that drugs proven useful in epilepsy often prove to be
useful in other nervous system disorders opens even larger markets
As hefinished his presentation, he noted that “The logic of winning
is attacking where competitors are absent Many large pharma
compa-nies have abandoned nervous system development because it was too
hard This opens the opportunity for smaller competitors with novel ap-proaches to drug invention to pick an initial serious indication like epi-lepsy where animal models, human models, and clinical trials in concert work tofind effective therapeutics, displace older less effective thera-peutics, then expand to additional indications Epilepsy is a place where you can win”
3.3 The NINDS ASP: yesterday, today, and tomorrow John Kehne, PhD, Program Director, National Institutes of Health, National Institute of Neurological Disorders and Stroke; H Steve White, PhD, Professor and Director, Anticonvulsant Drug Development Program, University of Utah
Dr John Kehne and Dr H Steve White discussed the National Insti-tute of Neurological Disorders and Stroke (NINDS) Anticonvulsant Screening Program (ASP) Dr Kehne is a Program Director at NINDS and Head of the ASP, and Dr White is Professor and Director of the Anticonvulsant Drug Development (ADD) Program at the University of Utah Dr Kehne started the presentation by pointing out that the ASP provides free compound testing to academia and industry through
a contract between NINDS and the University of Utah Since it was established in 1975, the ASP has contributed to nine“third generation” marketed AEDs
He then provided an overview of the ASP testing workflow In the initial identification phase, compounds are tested against maximal elec-troshock seizures, the 32-mA 6-Hz test, the corneal-kindled mouse, and
on a behavioral toxicity test Active compounds are further tested for initial differentiation using pharmacoresistance models, e.g., the
44-mA 6-Hz test, the bursting hippocampal slice, and the lamotrigine-resistant kindled rat, and for effects on seizure threshold using the IV pentylenetetrazole test Active compounds advance to full differentia-tion, which currently includes efficacy in a post-status epilepticus (SE) epileptic rodent model and evaluation for effects on cognition in a long-term potentiation test and in the Morris water maze assay In addi-tion to this“standard track” serial screening protocol, a new “special projects” track allows flexibility for assessing novel therapeutic mecha-nisms Lastly, Dr Kehne highlighted the PANAChE (Public Access to Neuroactive and Anticonvulsant Chemical Evaluations) Data Sharing Initiative; a publicly accessible database for nonconfidential data and in-formation from the ASP developed as a tool to further stimulate epilepsy drug discovery The database was released at the December 2013
annu-al meeting of the American Epilepsy Society and currently contains 150 literature reference compounds[10]
Dr H Steve White's lecture provided a snapshot of models under evaluation by the ASP Specifically, he highlighted the intrahippocampal kainite mouse model for mesial temporal lobe epilepsy, as well as a battery of tests to evaluate cognitive liability He focused on Theiler's virus mouse model of encephalitis-induced epilepsy and then the novel stress-free approach to the chronic delivery of AEDs to“newly di-agnosed” epileptic rats using a recently designed automated feeder sys-tem Dr White summarized the presentation by stating that the mesial temporal lobe epilepsy mouse, Theiler's murine encephalomyelitis virus model, and the battery of cognitive tests, once fully implemented, will aid in the differentiation of promising investigational drugs submitted
to the ASP Moreover, the automated feeder system provides a unique and stress-free mechanism for the chronic delivery of a drug to epileptic rats and provides a novel solution to chronic oral-dosing studies New models and approaches are directly addressing the recommendations
of the 2012 NINDS working group report and expanding the testing ar-mamentarium of the ASP
3.4 Epilepsy therapies: accomplishments and challenges Roger J Porter,
MD, Chief Scientific Officer, Epilepsy Foundation
Dr Roger J Porter, EF CSO, discussed the challenges of trying to guide
a compound to a successfully approved drug that can help patients with epilepsy He started by defining the valley of death This is
Trang 4basically the time in a compound's development between its screening
for potential use in epilepsy to a clinical trial He highlighted that the
Epilepsy Foundation has helped by funding 60 of 123 potential epilepsy
compounds through its Epilepsy Therapy Pipeline initiative He then
asked the question, are we taking enough risks? He noted that in
com-parison to other conditions, epilepsy has $5.3 million with regard to
annual research compared to $61 million for Parkinson's disease and
$40 million for multiple sclerosis and muscular dystrophy— two other
diseases that affect far fewer patients Clearly, the epilepsy community
needs to drive clinical research Mechanisms exist and we are well
primed to take advantage of this, but we need to invest in platform
part-nerships and even consider crowdfunding Hefinished the talk by
reminding the audience that there is a massive underserved population
of persons with epilepsy that needs our help
4 Session 3: early stage drug pipeline: proof of principle through IND
The conference then moved to discussion of treatments in the early
stage of the pipeline, with 12 presentations by companies with products
that are currently in the stage of development between proof of
princi-ple and clinical trials
4.1 Intellimedix Novel approaches to drug discovery with applications to
epilepsy and mitochondrial disease Jeffrey Skolnick, PhD, Scientific Advisor,
Intellimedix; Director of the Integrated Biosystems Institute at Georgia
Institute of Technology
Jeffrey Skolnick, PhD, who is the Director of the Center for the Study
of Systems Biology at the Georgia Institute of Technology, presented on
behalf of Intellimedix This system is a high throughput screening
ap-proach currently being used for epilepsy with specific emphasis on
Dravet syndrome and mitochondrial disorders He noted the strategy
of using computational analysis as a screening tool and then moving
to zebrafish models and on to small-scale clinical trials He emphasized
the importance of this tool by citing successful examples such as the
screening of progesterone using the zebrafish Dravet model as well as
mifepristone Moreover, the company is utilizing calcium imaging to
classify seizure type and testing to assess antiepileptic mechanism of
action
4.2 Asklepios BioPharmaceutical, Inc Galanin gene delivery for
temporal lobe epilepsy Cynthia Rask, MD, Chief Medical Officer,
Asklepios BioPharmaceutical, Inc
Dr Cynthia Rask of Asklepios BioPharmaceutical discussed
gala-nin gene delivery for mesial temporal lobe epilepsy This company is
developing gene delivery technology based on adeno-associated virus
(AAV) to deliver therapeutic genes Because galanin has been shown
to attenuate seizures and cell death in multiple animal models, they
are working to utilize efficient viral vectors to deliver the galanin gene
to a seizure focus in the temporal lobe Their goal is to achieve optimal
transduction of cells constituting a localized expression of the inhibitory
factor, galanin Delivery of the gene transfer product is achieved by
ste-reotactic injection into a defined seizure focus to attenuate local seizure
activity There are three classes of galanin-signaling receptors, and she
pointed out in the early studies that infusion of galanin into the CNS
sig-nificantly attenuated seizure activity in a number of animal models
[11–13] Proof-of-concept studies are in the public domain, and dose
es-calation studies to determine the upper limit that can be delivered are
completed[14–17] Currently, the company is evaluating a delivery
sys-tem with Medtronic Preliminary nonhuman primate and sheep studies
are completed Definitive dosing studies (in rodents and nonhuman
pri-mates), as well as the toxicology and biodistribution studies that are
re-quired prior to conducting studies in humans, are currently being
planned
4.3 AurimMed Pharma, Inc AMP-X-0079 Amir Pesyan (presented by Roger J Porter, MD in Dr Pesyan's absence), Chairman and Chief Executive
Officer, AurimMed Pharma, Inc
Amir Pesyan, Chairman and CEO of AurimMed Pharma, Inc., discussed the compound AMPX-0079 AMP-X-0079 has been shown
in in vivo studies to be orally and parenterally bioavailable, fast-acting (rapid oral absorption within 15 min), with a reasonably long pharma-cological half-life in animal models, and able to pass through the blood– brain barrier, thereby manifesting its pharmacological effects directly in the CNS This compound has been tested using Cerep® Full-BioPrint It has no significant activity at any Cerep® targets It is a CYP450substrate with no P-glycoprotein inhibition The chemical lacks side effects asso-ciated with any Cerep® targets, suggesting a novel mechanism of action AMP-X-0079 is effective in the only two validated models for partial epilepsy, MES and kindling In addition, AMP-X-0079 is effective in vir-tually all other models of epilepsy, including the lamotrigine-resistant amygdala-kindled rat and, most recently, in the mesial temporal lobe epilepsy (MTLE) mouse, in which classical AEDs are ineffective, imply-ing substantial broad-spectrum activity
The immediate plans for this product are phenotypic screening and prediction of sedative side effect The company will determine whether AMPX-0079 exhibits a functional similarity to known sedative compounds If yes, at what concentration does it exhibit a functional similarity to known sedative compounds? Their future plans are to cre-ate IND-enabling studies for genetic, general, toxicology, analytical, and safety pharmacology There are development challenges with regard to funding, and the company is looking for help with this
4.4 BioCrea GmbH LT GABAA PAMs for refractory epilepsy Norbert Hoefgen, PhD, Vice President Discovery, BioCrea Germany
Dr Hoefgen presented LT GABAA PAMs for the treatment of
refracto-ry epilepsy GABAA PAM has a novel GABAA beta mechanism of action The long-term effective site of action for GABAA PAM is different than the benzodiazepine receptor site This compound interfaces at the alpha beta 2-receptor site GABAA PAM shows activity at extrasynaptic GABAA receptors, which are resistant to benzodiazepine action Thus, these compounds could be useful for treating refractory epilepsy, refrac-tory status epilepticus, and Rett syndrome Moreover, these drugs are highly differentiated from traditional benzodiazepines and may be syn-ergistic with existing therapeutic compounds Hoefgen stated how these compounds appear to have a broad-spectrum anticonvulsant ef fi-cacy in animal models, superiority in models of refractory epilepsy, and relative freedom from the development of tolerance with twice-daily dosing[18–20] The data support a therapeutic value of long-term GABAA PAMs for the long-term treatment of epilepsy with excellent ef-ficacy, lack of tolerance, good therapeutic index, good oral availability, and low risk of drug interaction He further stated that the lack of devel-opment of tolerance together with activity at the extrasynaptic GABAA receptors suggests potential as a prime treatment for status epilepticus, and the company is looking for partners to help bring this compound to market
4.5 Epalex Inhaled treatment for refractory epilepsy Michael Rogawski,
MD, PhD, Professor, Department of Neurology, University of California, Davis
Dr Michael Rogawski provided information on an inhaled treatment
to stop seizures once they start in the brain but before they spread to be-come more severe, which is being developed in collaboration with Epalex Corp Propofol hemisuccinate (PHS), a proprietary propofol prodrug, has been formulated for pulmonary delivery by nebulization The concept is that PHS would be self-administered during a seizure aura to prevent the localized seizure discharge from progressing to a full-blown seizure or by a caregiver to terminate seizure clusters or
Trang 5status epilepticus Animal studies have shown that intrapulmonary
PHS has potent, broad-spectrum antiseizure activity[21] Inhalation
toxicology studies in rats demonstrated that intratracheal PHS does
not cause histopathological changes in the lung In collaboration with
NINDS and NIH's National Center for Advancing Translational Sciences
(NCATS), clinical-grade PHS has been manufactured, and a proprietary
clinical formulation has been developed Nonclinical studies are being
completed that will enable PHS to enter clinical trials This work is partly
supported through the NCATS BrIDGs (Bridging Interventional
Develop-ment Gaps) program
4.6 Fluorinov Pharma Inc FV-082: a safer orally active broad-spectrum
antiepileptic drug candidate Malik Slassi, PhD, President and Chief
Scientific Officer, Fluorinov Pharma Inc
Dr Malik Slassi, President and CSO of Fluorinov Pharma, discussed
the progress of one of their three lead AED candidates, FV-082, an orally
active broad-spectrum AED He emphasized that FV-082 was a unique
chemotype with a novel mechanism of action This chemical displays a
broad spectrum of efficacy profile and is very well tolerated in multiple
epilepsy animal models Dr Slassi noted that FV-082 exhibits a superior
preclinical safety profile when compared with leading AEDs[18,22,23]
It also demonstrated robust activity in amygdala-kindled rats,
suggest-ing potential clinical efficacy for the treatment of complex partial
seizures
FV-082 selectively modulates the Nav1.8 channel, androgen
recep-tor (AR), and MAOB region with no activity in over 100 related targets
Further studies are ongoing Preliminary safety data on this compound
show lack of typical deep sedation, and it is well tolerated in different
species up to 1000 mg/kg with only very mild clinical signs reported
There were no abnormalities in terms of liver function enzyme
eleva-tions and no weight gain, and other neurological signs were similar to
vehicle controls Besides its broad spectrum AED potential, the
com-pound has robust efficacy in models of inflammatory and neuropathic
pain
Dr Slassi summarized by saying that this compound is a new AED
chemically unrelated to current AEDs with an excellent safety profile
in the mouse, rat, and dog The drug inhibits the voltage-gated sodium
channel Nav1.8 and interacts with AR and MAOB It has an excellent
PK profile in rats and dogs In animal seizure models, it possesses a
broad-spectrum profile, and it demonstrated efficacy in models of
neu-ropathic and inflammatory pain The plans for testing this compound in
human clinical trials are underway
4.7 NeuroGate Therapeutics, Inc Extended neuroamides Harold Kohn,
PhD, Kenan Distinguished Professor, Division of Chemical Biology and
Medicinal Chemistry, University of North Carolina; Eshelman School
of Pharmacy and Department of Chemistry, University of North
Carolina–Chapel Hill; Founder, NeuroGate Therapeutics, Inc
Harold Kohn, PhD, Kenan Distinguished Professor, the Division
of Chemical Biology and Medicinal Chemistry at the UNC Eshelman
School of Pharmacy and Department of Chemistry, provided
infor-mation about extended neuroamides (ENAs) Extended
neuro-amides are novel drug candidates for epilepsy and pain that control
neuronal hyperexcitability[22,24] He noted that ENAs strategically
combine pharmacophores found in functionalized amino acids (FAAs),
such as lacosamide (Vimpat®), withα-aminoamides (AAAs), such
as safinamide and ralfinamide Both FAAs and AAAs are potent
anticon-vulsants It is believed that the targets for ENAs are sodium channels
with potential benefit for pathological states such as seizures, pain,
and other neurological conditions The ENAs exhibit excellent activities
in multiple, validated animal seizure models and displayed minimal
neurotoxicity at high doses They also displayed good drug properties
with high bioavailability, low clearance rates, and high
brain-to-plasma ratios He emphasized the lower development risk for these
drugs as they were designed using validated pharmacophores and that these molecules served as functional inhibitors of sodium channels that potently transition sodium channels to the slow inactivated state and show frequency use-dependent inhibition at therapeutically acces-sible concentrations, thus providing greater control of neuronal hyperexcitability
4.8 NeuroGenomeX, Inc 2DG Thomas P Sutula, MD, PhD, Founder, Chief Technical Officer and Director, NeuroGenomeX, Inc
Dr Sutula, Professor and Chair of the Department of Neurology at the University of Wisconsin and the Founder and CTO of NeuroGenomeX, Inc., discussed the novel anticonvulsant disease-modifying antiepileptic and neuroprotective effects of 2-deoxyglucose (2DG) with therapeutic opportunities for epilepsy and traumatic brain injury The 2DG is a glu-cose analog with novel neuroprotective and anticonvulsant disease modifying effects on plasticity[25] Preclinical efficacy studies in
epilep-sy are completed Delivery of 2DG to neurons and circuits is activity de-pendent, which is a novel advantageous property for an anticonvulsant Currently, the company has two US patents issued for epilepsy and a US patent for traumatic brain injury The drug has favorable animal toxicity and human toxicology Potential clinical uses include intractable
epilep-sy, seizure clusters, status epilepticus, and traumatic brain injury The company is funded by the Epilepsy Therapy Project–Epilepsy Research Foundation for an initial clinical trial to assess tolerability and efficacy
of 2DG in intractable epilepsy
4.9 INSYS Therapeutics, Inc Synthetic CBD Mark W Davis, Senior Director, Clinical, INSYS Therapeutics, Inc
Mr Davis, Senior Director, Clinical, INSYS Therapeutics, Inc., ex-plained the use of pharmaceutical cannabidiol (CBD) for epilepsy He introduced INSYS Therapeutics and noted recent successful anecdotal cases of marijuana usage with a high ratio of CBD for multiple indi-cations in epilepsy They havefiled (and since received) orphan drug designations in two indications — Lennox–Gastaut syndrome and Dravet syndrome The company will be conducting clinical studies in epilepsy and is currently working with leading universities and re-searchers on pilot studies to investigate cannabidiol usage across a vari-ety of indications INSYS' cannabidiol is produced via synthetic reaction and HPLC purification for a product that is ≥99.5% cannabidiol There is
no use of plant-based materials It is consistently reproducible and manufactured in the United States Other INSYS products currently available include generic dronabinol and Subsys® (fentanyl sublingual spray)
4.10 NeuroAdjuvants, Inc Galanin receptor 2-based therapy H Steve White, PhD, Professor and Director, Anticonvulsant Drug Development Program, University of Utah
Dr H Steve White provided a synopsis of galanin receptor 2-based therapy The specific highlighted compound was NAX 810-2, a novel galanin receptor 2 preferring neuropeptide analog for the treatment of epilepsy and pain This modified neuropeptide is metabolically stable and blood–brain barrier permeable Unlike galanin receptor 1-prefer-ring compounds, the preclinical profile of NAX 810-2 shows no effect
on plasma glucose levels at therapeutic doses Moreover, NAX 810-2 possesses a favorable CYP induction and inhibition profile with potent analgesic activity in several animal models Several preclinical develop-ment activities are planned including broad receptor screening and dose-ranging toxicology and pharmacokinetic studies in rats A pre-IND meeting with the FDA is also planned The goal for this drug is to
be parenterally available
Trang 64.11 University of South Florida Ketogenic compounds for the treatment
of epilepsy Dominic D'Agostino, PhD, Assistant Professor, Hyperbaric
Biomedical Research Laboratory
Dr D'Agostino reviewed the use of the high
fat/carbohydrate-restricted ketogenic diet (KD) and its importance for the metabolic
management of seizures through the elevation of specific ketone bodies
Ketone supplementation represents a strategy to circumvent the dietary
restriction associated with the KD and produces a therapeutic ketosis
independent of carbohydrate restriction[26] Ketone supplements
have been created that can produce rapid (15 min) and sustained
(N8 h) nutritional ketosis[27] Ketone esters and ketone mineral salts
are pending FDA Generally Recognized as Safe (GRAS) approval and
there is a phase I pilot study planned within one year
4.12 SciFluor Life Sciences LLC SF0034: a potent and selective KCNQ2/3
activator as a potential antiepileptic drug Scott Edwards, PhD, Vice
President and General Manager, SciFluor Life Sciences LLC
Dr Edwards, Vice President and General Manager of SciFluor Life
Sciences, introduced SF0034, a potent and selective KCNQ2/3 activator
This potential AED was created by strategic incorporation offluorine to
modulate binding properties Specific fluorine substituents result in a
compound with significantly increased potency and selectivity for
KCNQ2/3, potentially eliminating the urinary retention and cardiac
safe-ty issues of ezogabine and which is much less susceptible to blue
discol-oration than ezogabine This proprietary new chemical entity has an
extensive preclinical dataset, including assessment by the NINDS ASP,
and a 12-month path to the IND The key development challenge is to
show that this new chemical entity has mitigated the skin and eye
tox-icity that resulted in recent label restrictions for ezogabine The
compa-ny has established several academic collaborations to further assess
SF0034 and is looking for development and partnering opportunities
to bring the compound to market for epilepsy
4.13 Sage Therapeutics SAGE 547 for status epilepticus Jeffrey M Jonas,
MD, Chief Executive Officer, Sage Therapeutics
Dr Jonas, CEO of Sage Therapeutics, introduced SAGE-547
injec-tion (allopregnanolone), a novel compound for the management of
super-refractory status epilepticus SAGE-547 has displayed activity in
benzodiazepine-resistant seizure models targeting the alpha-4 subunit
of the GABAAreceptor A phase I/II study in refractory status epilepticus
is currently underway with 20 participating clinical sites Preliminary
data from thefirst four patients with severe status epilepticus, arising
from varying conditions, revealed promising clinical activity
5 Session 4: early-stage diagnostic devices and product pipeline:
new concepts and initialfindings
This session consisted of six presentations by representatives of
companies with devices under development or that are available
com-mercially for the detection of seizures The presentations were followed
by a panel session on user perspectives of seizure detection and alerting
devices
5.1 Cyberonics ProGuardian REST™: an innovative, in-home device system
designed to monitor, detect, and log night-time seizure activity Laurie
Groven, Global Medical Device/Diagnostic Marketing and Sales Executive,
Cyberonics
Laurie Groven, Global Medical Device/Diagnostic Marketing and
Sales Executive and Program Head of ProGuardian at Cyberonics,
pre-sented ProGuardian REST™, a device currently under investigation
The ProGuardian system is based on similar cardiac-based seizure
de-tection technology that is found in the company's AspireSR™ generator
for VNS therapy, which received CE Mark approval in February 2014 The technology has been further modified to provide caregivers, such
as parents of children with epilepsy, an in-home nocturnal seizure detection system Based on Cyberonics' data showing a correlation between generalized seizures and ictal tachycardia, ProGuardian was designed to monitor changes in heart rate It also monitors motion Al-gorithms have been designed to determine whether a particular pattern
of heart rate changes and movement could represent a seizure and if so, audible and visual notifications are generated for the caregiver Sensitiv-ity settings for both heart rate and movement detection can be adjusted
by the end user Operationally, before the patient goes to sleep, a sensor will be attached to aflexible, single-use patch that is applied to the chest, after which the sensor automatically begins to monitor heart rate and establish a communication link with a hub to which seizure
no-tifications are sent upon algorithmic confirmation for the caregiver The hub needs to be within 30 ft of the patient— if the caregiver is further away, an optional Android smartphone app will be able to send noti fica-tions throughout a wi-fi-enabled home Confirmed seizures are elec-tronically logged within the hub, which can generate a report for later review Daytime seizures can be manually added to make the reports more comprehensive
5.2 Brain Sentinel™ EMG-based convulsive seizure detection and warning system José E Cavazos, MD, PhD, Vice President, Medical Affairs, Brain Sentinel, LGCH, Inc
Dr Cavazos, VP, Medical Affairs, and Co-Founder, LGCH, Inc dba Brain Sentinel™, discussed the Brain Sentinel™ seizure detection, anal-ysis, and warning system, which is intended for use in the home, seizure monitoring units, and long-term care facilities such as nursing homes It aims to detect seizures based on using surface electromyogram (EMG) recording of the biceps muscle to detect patterns consistent with mus-cular contractions during seizures such as generalized tonic–clonic sei-zures It is currently undergoing evaluation in a multicenter, phase III, pivotal clinical trial of its sensitivity and false detection rate compared
to multiple reviews of the same subjects' video-EEG recordings The de-vice consists of an EMG sensor that communicates via wi-fi with a base station, which in turn alerts caregivers nearby when a seizure is
detect-ed basdetect-ed on algorithmic analysis of the surface EMG The system in-cludes a microphone to record sounds occurring during seizures Alerts can also be sent via phone, text, or email to caregivers or to sum-mon emergency services All EMG recordings, including marked periods
of ictal EMG, will be saved and stored in near real-time in the cloud, which could assist the patient's clinician in the determination of seizure semiology (e.g., tonic, clonic, or tonic–clonic) and hence potentially in the selection of therapy
5.3 Epitel, Inc Wireless EEG patch Mark Lehmkuhle, PhD, Chief Executive
Officer, Chief Technology Officer, Epitel, Inc., Research Assistant Professor, Department of Neurosurgery, University of Utah
Dr Lehmkuhle, CEO, CTO, Epitel, Inc., Research Assistant Professor, Department of Neurosurgery, University of Utah, described a wireless EEG patch under development by Epitel, Inc The goal of the EEG patch
is to augment patient self-report of seizure occurrence in diaries with
a quantitative, electrographic report of when seizures occurred and how long they lasted The current prototype is based onflexible circuit boards, has two gold electrodes that are attached on the scalp (at loca-tions guided by an individual patient's prior EEG studies), is covered
byflexible urethane, and logs and transmits EEG data for over three days The prototype is currently being evaluated in the neurocritical care unit at the University of Utah, and recordings have demonstrated clean and artifact-free EEG Once applied to the scalp, it begins to log and transmit EEG data immediately Multiple devices could be placed
on the scalp if needed Efforts are now underway to make a disposable EEG patch that is 1″ by 1″ by 0.25″ with the two electrodes separated
Trang 7by 24 mm, extend recording time to seven days, and make it waterproof
with polyamide encapsulation The technical challenge of making the
electrode–scalp interface watertight over the duration of the recording
and at the same time ensuring that the electrode gel does not dry out
can be addressed by adding a nonstandard adhesive for the part of the
patch not occupied by the electrodes Candidate adhesives have been
identified which can be removed with acetone at the conclusion of the
recording The company plans to test this new design in patients in
the home setting
5.4 Empatica Embrace: autonomic and seizure events— personalized
monitoring and alerts Rosalind W Picard, ScD, Co-founder, Chief Scientist,
Empatica, Inc., Founder and Director of the Affective Computing Research
Group, Massachusetts Institute of Technology (MIT) Media Lab; Matteo
Lai, Co-founder, Chief Executive Officer, Empatica, Inc
Dr Picard, Chief Scientist, Empatica, and Mr Lai, CEO, Empatica,
discussed two sensor products worn on the wrist The“E3” is a device
available today for researchers, and the“Embrace” is a
consumer-facing device under development Both sensors measure motion,
tem-perature, and autonomic activity Autonomic activity captures both
branches of the autonomic nervous system: the sympathetic branch
through measurement of electrodermal activity (EDA) and the
para-sympathetic branch through measurement of blood volume pulse,
from which heart rate and heart-rate variability are computed Dr
Picard cited data from a 90-patient study at Boston Children's Hospital
showing that EDA was elevated more than 2 standard deviations
above preictal levels in 100% of generalized tonic–clonic seizures and
in 86% of complex partial seizures[28] She presented otherfindings
showing that combining EDA data with motion sensing increased
accuracy in detecting generalized tonic–clonic seizures compared with
motion sensing alone[29] In a study of 73 children with active epilepsy
recorded for a total of 3525 h, using a nonpersonalized detection
algo-rithm, 77% of the children had zero false detections, while 23% had
from 1 to 16 false detections, with an overall mean ofb0.74/day
Fur-ther, she presented data showing that the magnitude of the ictal EDA
change correlates significantly and positively with the duration of
postictal generalized EEG suppression, an EEG biomarker associated
with SUDEP in a published series of monitored SUDEP cases[30]
Mr Lai said that the current E3, which can stream data for up to 16 h,
connects wirelessly to a smartphone app, and securely sends data to
the cloud He also presented“Embrace”, a new consumer-facing device
being developed based on the E3, which will additionally provide
per-sonalized real-time alerts and insights for both patients and clinicians
to better understand and treat ictal events The Embrace will be the
first comfortably wearable seizure-alerting device to collect clinical
quality autonomic data in patients with epilepsy while providing an
im-portant biomarker correlated to postictal EEG suppression
5.5 Smart Monitor Automated seizure tracking and recording Anoo
Nathan, Chief Executive Officer, Smart Monitor
Ms Nathan, CEO, Smart Monitor, provided an update of
SmartWatch, a device that detects and alerts upon the repetitive
shak-ing motions caused by generalized tonic–clonic seizures (GTCSs) The
SmartWatch is available with a monthly subscription-based pricing
model Sixty percent of current users are under the age of 21 years In
addition to functioning as a wristwatch by telling time and the date,
SmartWatch utilizes algorithms to continuously monitor and analyze
motion and to determine if a pattern of repetitive shaking movements
may be representative of a GTCS Upon detecting patterns of abnormal
movement that may be representative of seizures, and in conjunction
with a companion smartphone, an alert is issued as a text message
and/or phone call that are automatically sent to caregivers or other
des-ignated alert recipients, providing the location of the patient based on
GPS These alerts go out within seconds after the onset of repetitive
shaking motion A panic button on the watch can be pressed by the pa-tient in case of an emergency or if they feel that they are about to have a seizure The SmartWatch supports additional functionality such as giv-ing the patient medication reminders, analyzgiv-ing sleep duration and quality, recording audio during seizure episodes, and providing analyt-ics and reporting/seizure tracking for physicians after data transmission
to back-end cloud-based servers Seizure-related data provided to phy-sicians include duration of the episode, severity (amplitude and fre-quency of the shaking movements), frefre-quency, time of occurrence, and associated audio Detailed tracking and counting of episodes and in-formative user dashboards provide a quick longitudinal overview of the individual's episodic activity A provided push-button allows the patient
to input when a non-GTCS (such as a complex partial seizure) has oc-curred and when medication was taken Ms Nathan mentioned that five pilot and field studies are underway and planned, including a pedi-atric study at LeBonheur Children's Research Hospital, a study at Stanford to integrate the SmartWatch-generated data with My Epilepsy Diary, a study at University of Virginia focused on reduction of adoles-cent anxiety and successful transition to adulthood in an outpatient set-ting, an inpatient study at Boston Children's Hospital of ictal autonomic biomarkers to assess SUDEP risk, and a study at New York University of the usefulness of the data for ongoing outpatient clinical care of patients with epilepsy A submission to the FDA for 510(k) clearance is under preparation
5.6 RTI International esap Kristin H Gilchrist, PhD, Research Scientist, Electronics and Applied Physics Division, RTI International
Dr Gilchrist, Research Scientist, Electronics and Applied Physics Di-vision, RTI International, discussed esap, a system that detects seizures based on a multi-parametric approach and an adaptive algorithm esap senses heart-rate patterns as recorded by electrocardiogram (ECG) as well as movement and respiration An initial study of 28 pa-tients at Children's National Medical Center completed in 2012 using postprocessing analysis demonstrated high detection accuracy for gen-eralized seizure types and 50% detection for partial seizures In late
2013, NIH funding was secured for trials at Children's National Medical Center using less burdensome hardware and technology capable of real-time detection The current prototype consists of a sensor (the Zephyr Biopatch) that is worn on the chest and which communicates via Bluetooth to a processing module An adaptive algorithm that“learns” from its successes and mistakes for a particular patient is being devel-oped and will eventually be integrated into the sensor to send an alarm locally or remotely
5.7 Panel session: seizure detection and alerting devices: are they ready for prime time?
Panel: Daniel Friedman, MD, Moderator, Assistant Professor of
Neurolo-gy, New York University, Comprehensive Epilepsy Center; Tom Stanton, Executive Director, Danny Did Foundation; Michelle Welborn, PharmD, President, Intractable Childhood Epilepsy (ICE) Alliance; Catherine Jacobson, PhD, Post-doctoral Fellow, Pediatric Epilepsy, University of California, San Francisco
Dr Friedman, Assistant Professor of Neurology, New York University, moderated a panel discussion that addressed the roles that noninvasive seizure detection devices may play in the management of epilepsy and seizure safety, the benefits of various detection methods and form fac-tors for different patient populations, the seizure types that are a prior-ity for detection, and optimal performance characteristics of these devices The panel participants were Tom Stanton, Executive Director, Danny Did Foundation; Michelle Welborn, PharmD, President, Intracta-ble Childhood Epilepsy (ICE) Alliance and parent of a child with epilep-sy; and Catherine Jacobson, PhD, Postdoctoral Fellow, Pediatric Epilepsy, University of California, San Francisco, and also a parent of a child with epilepsy
Trang 8Dr Jacobson stressed the importance of multiparametric systems
for detecting nonconvulsive seizures; especially systems that have
a low false-negative rate and which alert caregivers, particularly
parents whose children have nocturnal seizures Her child, for example,
experiences severe, nocturnal nonconvulsive seizures that last up to
15 min and can be associated with cessation of breathing, and so, on
a nightly basis, she is very concerned about the possibility of SUDEP
Dr Welborn's daughter also has a preponderance of seizures during
sleep She expressed the need for a system that could accurately predict
when a seizure was going to occur so that interventions could be
developed and used to prevent seizures before they started;
conse-quently, seizure-related complications, including SUDEP, would also
be prevented She too commented on the need for systems to detect
sei-zures other than generalized tonic–clonic seizures
Mr Stanton, whose nephew Danny died from SUDEP in 2009, works
through the Danny Did Foundation to educate parents and increase
awareness about the available seizure-detection systems In his
experi-ence, parents want to know which device they should use, how much
particular devices cost, what kinds of data are captured, and which
pa-rameters for seizure activity are measured He said many parents use
video- and audio-based baby monitors (and Dr Jacobson said that she
does as well so that she can see her son and assess if he is having a
sei-zure or not) Mr Stanton feels it is important for medical professionals
to share information with parents and adults with epilepsy about
de-vices in the same manner that they present options related to medicine,
surgery and diet, with the understanding that there is, currently, no
one-size-fits-all device solution
Regarding cost, Dr Welborn said ideally the costs should be covered
by insurance She also encouraged clinicians to consider recommending
private-duty nursing services for children with catastrophic epilepsies
who are at high risk for SUDEP from nocturnal seizures
6 Session 5: late-stage and approved devices—what is new?
This session consisted of 6 presentations about late-stage devices for
the treatment of epilepsy
6.1 Medtronic, Inc DBS therapy for epilepsy Jon Giftakis, PhD, Senior
Principal Scientist, Medtronic Neuromodulation
Dr Giftakis, Senior Principal Scientist, Medtronic Inc., talked about
deep brain stimulation (DBS) Deep brain stimulation therapy for
epi-lepsy is approved in various geographies outside of the U.S In the U.S.,
DBS therapy for epilepsy is under investigation and remains
unap-proved for commercialization The device consists of an implantable
pulse generator connected to stimulating electrodes placed in the
ante-rior nucleus of the thalamus (ANT) bilaterally The SANTE trial, which
evaluated DBS therapy for epilepsy, was published in 2010[31]
En-rolled patients have continued to be followed Five years of data
collec-tion has been completed and submitted for publicacollec-tion Discussions
continue with the FDA on options for regulatory approval in the U.S
Medtronic is developing a new neurostimulation device that is currently
in human studies and which has a built-in accelerometer to monitor
motion, patient-specific seizure detection algorithms, and the capability
to both stimulate and sense brain activity concurrently Further, it can
perform evoked potentials to determine if there is neural connectivity
between a therapy electrode and another remote electrode, such as an
electrode in the hippocampus, and the extent of excitability of that
re-mote site, which can in turn be modulated by stimulations by the ANT
electrode[32–34]
6.2 NeuroSigma, Inc eTNS Christopher DeGiorgio, MD, Professor of
Neurology, University of California, Los Angeles
Dr DeGiorgio, representing NeuroSigma, addressed noninvasive
trigeminal nerve stimulation with the eTNS™ system as an epilepsy
therapy He characterized this approach as neuromodulation, without implantation, of neural structures involved in seizures, mood, and atten-tion Mechanism-of-action studies using positron emission tomography have suggested that eTNS reduces metabolism in the temporal-parietal cortex and the mesial temporal regions and increases metabolism in the mesial frontal lobe, a region associated with mood and attention[35] A phase II, randomized, double-blind trial of eTNS was conducted in 50 patients with drug-resistant epilepsy who were randomized to active treatment or sham stimulation[36] A 40% responder rate was seen in the active treatment group at 18 weeks compared with a 16% responder rate in the control group The within-group change in responder rate was statistically significant in favor of active treatment (p = 0.0136), and the between-groups change in responder rate approached but did not quite meet statistical significance (p = 0.078) There were also
sig-nificant within-group and between-groups improvement in mood asso-ciated with active treatment His impression was that improvement in mood typically occurs before the improvement in seizure frequency Plans are underway for a pivotal phase III, multicenter trial as adjunctive therapy for drug-resistant complex partial seizures in up to 350 pa-tients, which will exclude data from thefirst 4 weeks of treatment (induction phase), during which epilepsy device trials have historically not shown significant efficacy compared to placebo The planned
prima-ry endpoint is percent change in seizure frequency from baseline to end
of 12 weeks of continued treatment, which begins after the 4-week in-duction period Secondary endpoints include responder rate, RRATIO, mood, and quality-of-life measures The company is pursuing additional potential indications, including attention-deficit hyperactivity disorder, major depressive disorder, and posttraumatic stress disorder
6.3 University of California, Los Angeles Ultrasound for seizure modulation John Stern, MD, Department of Neurology; Director, Epilepsy Clinical Program and Co-Director, Seizure Disorder Center, University of California, Los Angeles
Dr Stern, Director of the Epilepsy Clinical Program at UCLA, discussed low-intensity focused ultrasound (LIFUP) for the treatment
of temporal lobe epilepsy (TLE) As opposed to high-intensity focused ultrasound (HIFU), low-intensity ultrasound modulates brain activity without imparting significant thermal energy to bone or brain tissue The mechanism is presumed to be exerted by a biomechanical effect
on neuronal membranes which impacts excitability in one direction or another depending on the pulse width and frequency that are used, as demonstrated in animal studies with functional MRI[37–39] An advan-tage of this technique over transcranial magnetic stimulation is that deep brain structures can be targeted In a rodent PTZ model of acute seizures, LIFUP decreased seizures compared to controls, and histologi-cal analysis of the treated brains showed no evidence of tissue destruc-tion, as compared to HIFU, which ablates brain tissue[40] Dr Stern's group plans to study the safety of LIFUP using an MRI-compatible LIFUP device in patients with TLE who are candidates for standard ante-rior temporal lobe resection This patient group was identified in part because the bone overlying the target is relatively thin Study subjects will undergo LIFUP with simultaneous fMRI, and will also have an EEG obtained prior to and after LIFUP and neuropsychological testing after LIFUP After a period of approximately 1 week, the study subjects will undergo the planned anterior temporal lobe resection Resected tissue will be examined histologically to evaluate for any potential histopath-ologic effects of LIFUP
6.4 Visualase, Inc Laser ablation in neurosurgery Ashok Gowda, PhD, Founder and Chief Operating Officer, Visualase, Inc
Dr Gowda, Founder and COO of Visualase, provided an update on their Visualase device, which is cleared for marketing as a surgical tool for soft tissue ablation in neurosurgery Visualase entails a real-time, MRI-guided, laser-based thermal ablation technique that targets the
Trang 9brain tissue that has been identified as a patient's seizure focus The
disposable laser applicator, 1.65 mm in diameter, consists of a
laser-diffusingfiber and an outer cooling catheter, and is inserted through a
small access hole that is made in the skull Therefore, unlike resective
surgery, this device does not require a craniotomy A workstation
gener-ates the 980-nm diode laser and interfaces with an MRI machine to
provide real-time thermal feedback during the procedure to enable
the surgeon to limit tissue damage to the intended structure Patients
typically remain in the hospital for one night The technology,
origi-nally developed to target brain tumors, has been used in patients
with difficult-to-access deep-seated lesions, such as hypothalamic
hamartomas, and approximately 70 patients have been treated as of
this presentation Dr Gowda said that the neurosurgeon who has
per-formed the largest number of procedures on these lesions has publicly
reported a 93% seizure-free rate among his treated patients Other
tar-gets for this therapy have included mesial temporal structures
(amyg-dala and hippocampus), focal cortical dysplasias, and tubers, including
multiple tubers treated in the same patient, either during the same
ses-sion or serially In total, over 400 patients with epileptic foci have
under-gone the Visualase procedure as of this presentation, and about half are
adults and the other half children Outcome results are being collected
by a number of investigators, though they have not yet been analyzed
6.5 Swedish Neuroscience Institute MRI-guided focused ultrasound for
treatment of mesial TLE John Snell, PhD, Technical Director—Brain
Program, Focused Ultrasound Foundation, Swedish Neuroscience Institute
Dr Snell, Technical Director—Brain Program, Focused Ultrasound
Foundation, discussed MRI-guided focused ultrasound as a therapy for
mesial TLE The device thermally ablates brain tissue and is also
current-ly under evaluation for the treatment of essential tremor, Parkinson's
disease, and other CNS disorders where the targets are deep, such as
the thalamus A study using cadaver skullsfilled with gel-mimicking
phantom material suggests that clinically significant heating can be
pro-duced in regions corresponding to the hippocampus and amygdala In
these experiments, significant heating of the bone underlying the region
corresponding to the hippocampus was observed, especially the petrous
bone, and particularly with 30-second sonication A shielding technique
has been devised to lessen skullfloor heating Based on this feasibility
work, plans are underway to proceed with clinical development and
to move towards lower-frequency transducers and better focusing
tech-niques for lateral targets
6.6 Boston Children's Hospital Transcranial magnetic stimulation
Alexander Rotenberg, MD, PhD, Director, Neuromodulation Program,
Associate Professor of Neurology, Boston Children's Hospital, Harvard
Medical School
Dr Rotenberg, an epileptologist at Boston Children's Hospital,
pre-sented transcranial magnetic stimulation (TMS) for the treatment of
epilepsy Transcranial magnetic stimulation is a method for focal
brain stimulation with small intracranial electrical currents that are
generated by a powerful magneticfield Uniquely among brain
stimula-tion methods, TMS has robust diagnostic and therapeutic capacities that
are relevant to the study and management of epilepsy Transcranial
magnetic stimulation protocols can be divided into three categories:
re-petitive TMS (rTMS), which modulates brain excitability; single-pulse
TMS (spTMS), which evokes a motor response or other observable
change in cortical function; and paired-pulse TMS (ppTMS), which is a
means to assess the excitation:inhibition ratio[41,42] In common
spTMS and ppTMS protocols, a hand-held electromagnetic coil is
posi-tioned next to the scalp and generates a brief, approximately 2-Tesla,
magneticfield, which induces an electrical current in the nearby cortex
[41] When the motor cortex is targeted, the resultant limb movement
can be quantified with surface EMG, which serves as confirmation that
the motor cortex has been stimulated or as a measure of motor cortex
excitability Both clinical and preclinical epilepsy research with TMS are ongoing in Dr Rotenberg's Neuromodulation Program[43]
Clinical-ly, his group uses TMS to localize motor and language function to help the neurosurgeon plan the extent of resection for epilepsy surgery can-didates whose seizure focus is close to motor or language cortical areas
He is also studying the effects of TMS in patients with unilateral or bilat-eral TLE using customized magnetic coils that can induce electrical cur-rents deeper in the brain than is achievable with conventional coils Preliminary data are encouraging in terms of efficacy, tolerability, and safety (adverse events and memory function)
7 Session 6: Nonprofit Organizations, Government, and Crowdfunding—Grants, Awards and Funding to Advance Research to the Next Critical Stage
Panel: Roger J Porter, MD, Moderator, Chief Scientific Officer, Epilepsy Foundation; Jan Buelow, RN, PhD, Vice President, Programs and Research, Epilepsy Foundation; Rajesh Ranganathan, PhD, Director, Office of Transla-tional Research, NaTransla-tional Institute of Neurological Disorders and Stroke;
H Steve White, PhD, Research Director, Citizen's United for Research in Ep-ilepsy (CURE), Professor and Director, Anticonvulsant Drug Development Program, University of Utah; Bre DiGiammarino, Cause Director, Indiegogo
Dr Porter, CSO, Epilepsy Foundation (EF), chaired a panel session that addressed funding mechanisms to advance epilepsy-related re-search to the next critical stage of development
Dr Buelow presented the new approach to research funding at the EF which resulted from the merger of EF with the Epilepsy Therapy Project The EF is moving from traditional research grants to a strategy
of driving research to bring treatments to patients more quickly To achieve this strategy, successful programs such as new therapies grants are continuing New funding mechanisms are being introduced, includ-ing support for postdocs workinclud-ing in innovative environments and rolling seed grants to address timely topics In addition, working coop-eratively with other key stakeholders through partnerships is a major focus The overall goal of EF, as an organization that advocates for pa-tients with epilepsy and their families, is to be a leader in cutting-edge research to benefit the community
Dr Ranganathan outlined the changes underway at NINDS to sup-port translational research Based on the concept that translation begins and ends with the patient, their guiding principles are to get therapeu-tics to people; establish a fail-early, fail-fast approach to portfolio man-agement; and work with partners to hand off de-risked projects for downstream funding Two programs have supported the bulk of their translational research efforts: Cooperative Program in Translational Research (U01) and the trans-NIH Blueprint Neurotherapeutics (BPN) The NINDS is now evolving these programs to achieve an integrated vi-sion to further advance small molecules, biologics and biotech products, and devices Announcements from NIH about these new programs were released in July 2014, with thefirst grants awarded starting in June 2015
Dr White discussed CURE's research programs, which are based on CURE's mission tofind a cure for epilepsy and to raise awareness of the prevalence and devastation caused by epilepsy— in short, no sei-zures, no side effects, no exceptions As the largest nongovernmental funder of epilepsy research ($20,802,464 in 174 awards between 2000 and 2014), CURE has four priority research areas: the basic mechanisms
of epileptogenesis, the multifaceted causes of epilepsy, the pediatric epilepsy syndromes, and new animal models of epilepsy There is a concerted effort to invest in high-risk, scientifically sound research proposals that have the potential of being transformative The most re-cent initiative, launched in May 2014, is the Epilepsy Genetics Initiative The goal is to develop an exome/genome sequence database of clinical generated sequences and associated phenotyping data The data will
be analyzed every six months andfindings reported back to patients' physicians in an effort to identify the cause of a patient's epilepsy In
Trang 10addition, the database will serve as a resource for scientists to drive
fur-ther research
Ms DiGiammarino defined crowdfunding as the collective effort of
individuals who network and pool their money, usually via the internet,
to support efforts initiated by other people or organizations Indiegogo
was founded in 2008 and is the world's largest crowdfunding platform
Organizations run campaigns on the platform to amplify their existing
support, demonstrate interest in the organization, spread their message
and raise awareness, and engage the community The EF, for example,
has already partnered with Indiegogo to increase funding for SAMi, an
innovative movement monitor that previously received the EF Shark
Tank award
The session concluded with H Steve White, PhD receiving the
Life-time Accelerator Award, with remarks lauding his accomplishments
offered by Warren Lammert, Chair of the EF Board of Directors; Evelyn
Nussbaum, a member of the CURE Board of Directors; Roger J Porter,
MD, Chief Scientific Officer, EF; and Jacqueline French, Professor of
Neu-rology, New York University Dr White then expressed his profound
thanks and appreciation to the many people who have supported him
over his career
8 Session 7: new directions and opportunities in epilepsy research
In this session, scientists and representatives of the drug and device
private sector provided insight on the trends for the future of epilepsy
therapeutics
8.1 New directions in epilepsy research Daniel Lowenstein, MD, Robert B
and Ellinor Aird Professor and Vice-Chair of Neurology, Director, UCSF
Epilepsy Center, University of California, San Francisco
Dr Lowenstein gave the audience an exciting look into his personal
view of the major advances likely to make a significant impact in the
ep-ilepsyfield in the relatively near term The first area he highlighted was
that of optogenetics This technology uses light-sensitive proteins called
“opsins” to control seizures Scientists can tie the opsin genes to a
promotor that allows them to be incorporated into specific neurons
Once this is done, light can selectively activate specific cells and alter
their excitability Dr Lowenstein described an experiment carried out
by Dr Jeanne Paz and colleagues in which inhibitory opsins were placed
in the thalamic neurons of animals that had seizures due to a focal
cor-tical stroke[44] The investigators then created a closed-loop system
that turned on the light when the EEG showed a seizure, which
inhibited the thalamic neurons and instantly aborted the seizure This
is a very exciting technology that may allow seizure control without
medication
He next discussed the future impact of the explosion of knowledge
about epilepsy genetics He reminded us that in the“first era” of
epilep-sy genetics, the majority of genes discovered that were associated with
epilepsy were genes encoding ion channels This era has been termed
the“channelopathy era” by Dr Ingo Helbig[45] Recently, copy number
variation (CNV) has come to the forefront as a culprit in epileptic
en-cephalopathies[46] Now, Dr Lowenstein believes, as a result of a
num-ber of large genetic scientific collaborations, that we are on the verge of
a new era of genomic discovery For example, recent large-scale efforts
have led to the recognition of de novo mutations explaining upwards of
15% of epileptic encephalopathies[46] In the near future, the Epilepsy
Genetic Initiative (EGI), sponsored by the nonprofit Citizens United for
Research in Epilepsy (CURE) and the NINDS, will allow individuals to
“donate” their genetic data so that genes can be studied and restudied
Next, Dr Lowenstein highlighted thefield of pluripotential stem cell
research, which has now made it feasible to obtain cells from a patient's
skin biopsy, grow outfibroblasts, and then drive the cells to become
in-ducible pluripotential stem cells[47] If the patient has a gene mutation,
one could theoretically correct the mutation and thus modify the cells to
a“healthy state” and put them back in the patient Also, the cells could
be differentiated into neurons, which would create an assay system for the identification of specific drugs that might be effective for the individual from whom the cells were derived A research team led by
Dr Jack Parent has demonstrated that pluripotent stem cells derived from patients with Dravet syndrome and differentiated into neurons have abnormalfiring, a result the team has labeled “human seizures in
a dish”[48]
Dr Lowenstein also discussed the potential of drug screening in zebrafish Dr Scott Baraban and his colleagues have successfully shown that it is feasible to take a specific genetic mutation, such as the SCN1A mutation that leads to Dravet syndrome, place it in zebrafish, and observe the epilepsy phenotype[49] This elegant system allows for
a very effective, high-throughput system for screening candidate drugs, and this has already led to the discovery of some novel compounds that may soon be studied clinically
He then discussed some remarkable studies that have demonstrated the ability of transplanted inhibitory interneurons to prevent epilepto-genesis and associated comorbidities[48,50]and ended by briefly describing the Human Epilepsy Project (HEP), a multicenter observa-tional cohort study of patients with recently diagnosed focal epilepsy that will look for biomarkers of disease activity and treatment resistance [51]
8.2 Improving delivery of therapies in people who need them: an industry perspective Mark Evenstad, Chief Executive Officer, Upsher-Smith Mark Evenstad, the CEO of a privately held and family-owned phar-maceutical company that has a large focus on epilepsy, spoke about the complexity of the current system of getting medication to patients and observed that physician decisions to treat patients with a certain AED do not always translate into the patient actually getting the drug due to is-sues of access and cost He fears that this can often become a“system of
no”, where patients are unable to get optimal therapy This has
motivat-ed Upsher-Smith to implement a new business model designmotivat-ed to im-prove access to effective treatments and reduce health-care costs He encouraged the epilepsy community to work towards greater access op-portunities coupled with a focus on outcomes-driven health care 8.3 The role of corporate and government partnerships in developing new epilepsy products
Panel: Roger J Porter, MD, Moderator, Chief Scientific Officer, Epilepsy Foundation; Santiago Arroyo, MD, PhD, Vice President, Head of Clinical Re-search and Chief Medical Officer, Pharmatherapeutics, Worldwide Research
& Development, Pfizer, Inc.; Roy E Twyman, MD, Vice President and Head, Alzheimer's Disease Area, Janssen Pharmaceuticals R&D LLC; Michael Gold,
MD, Vice-President and Head of the CNS Practice, UCB, Inc.; Frank Fischer, Chief Executive Officer, NeuroPace, Inc
Dr Roger J Porter moderated a panel of four representatives of drug and device companies that have been or are currently focused on epi-lepsy development
Dr Santiago Arroyo, VP, Head of Clinical Research & CMO, Pharmatherapeutics, Worldwide Research & Development, for Pfizer Inc., discussed what big pharma looks for in a new drug for epilepsy
He stated that the top needs were for superior efficacy, differentiation, improved safety and tolerability, no need for titration, broad-spectrum activity, and– ideally – disease modification He went on to say that neurologists in the U.S and Europe believe efficacy is the #1 concern Usually, drugs produce 50% responders, but achieving 100% responders
is more critically important Because epilepsy is heterogeneous, he feels that there is a need for better understanding of who will be a responder, through biomarkers, or a better understanding of genetic variation Unfortunately, one may need tens of thousands of patients to determine this Echoing Dr Lowenstein's previous talk, he discussed the possibility
of treating patients with rare disorders through the use of pluripotent stem cells or as a“disease in a dish” He announced that Pfizer and